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Background— Renal insufficiency is associated with increased morbidity and mortality after cardiopulmonary bypass cardiac surgery. B-type natriuretic peptide is a cardiac hormone that enhances glomerular filtration rate and inhibits aldosterone. Cystatin has been shown to be a better endogenous marker of renal function than creatinine. Methods and Results— We performed a double-blinded placebo-controlled proof of concept pilot study in patients (n=40) with renal insufficiency preoperatively (defined as an estimated creatinine clearance of <60 mL/min determined by the Cockroft-Gault formula), undergoing cardiopulmonary bypass cardiac surgery. Patients were randomized to placebo (n=20) or IV low dose nesiritide (n=20; 0.005 μg/Kg/min) for 24 hours started after the induction of anesthesia and before cardiopulmonary bypass. Patients in the nesiritide group had an increase of plasma B-type natriuretic peptide and its second messenger cGMP with a decrease in plasma cystatin levels at the end of the 24-hour infusion. These changes were not observed in the placebo group. There was a significant activation of aldosterone in the placebo group at the end of the 24-hour infusion, but not in the nesiritide group. At 48 and 72 hours, there was a decrease in estimated creatinine clearance and an increase in plasma cystatin as compared with end of the 24-hour infusion in the placebo group. In contrast, renal function was preserved in the nesiritide group with no significant change in estimated creatinine clearance and a trend for plasma cystatin to increase as compared with end of the 24-hour infusion. Conclusion— This proof of concept pilot study supports the conclusion that perioperative administration of low dose nesiritide is biologically active and decreases plasma cystatin in patients with renal insufficiency undergoing cardiopulmonary bypass cardiac surgery. Further studies are warranted to determine whether these physiological observations can be translated into improved clinical outcomes.

Abstract The pool of hematopoietic stem cells that actively contributes to hematopoiesis is small, and the cells replicate slowly. Patients with paroxysmal nocturnal hemoglobinuria invariably have a mutation in the PIG-A gene, and many have more than one clone of PIG-A mutated cells. Typically there is a dominant clone and a smaller second clone. By using a combination of stochastic dynamics and models of hematopoiesis, we show that it is very unlikely that more than one PIG-A mutated clone arises at the level of the hematopoietic stem cells. More likely, the smaller clone develops in the progenitor cell pool that would be expected to contribute to hematopoiesis for a shorter period of time. We provide estimates for the duration of these contributions and testable hypotheses that can shed important insights on this acquired hematopoietic stem cell disorder. Disclosure of potential conflicts of interest is found at the end of this article.

Background— Ranolazine, a piperazine derivative, reduces ischemia via inhibition of the late phase of the inward sodium current (late I Na ) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Increased intracellular calcium leads to both mechanical dysfunction and electric instability. Ranolazine reduces proarrhythmic substrate and triggers such as early afterdepolarization in experimental models. However, the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans. Methods and Results— The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG (Holter) recording was performed for the first 7 days after randomization. A prespecified set of arrhythmias were evaluated by a core laboratory blinded to treatment and outcomes. Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had continuous ECG recordings that could be evaluated for arrhythmia analysis. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats (166 [5.3%] versus 265 [8.3%]; P <0.001), supraventricular tachycardia (1413 [44.7%] versus 1752 [55.0%]; P <0.001), or new-onset atrial fibrillation (55 [1.7%] versus 75 [2.4%]; P =0.08). In addition, pauses ≥3 seconds were less frequent with ranolazine (97 [3.1%] versus 136 [4.3%]; P =0.01). Conclusions— Ranolazine, an inhibitor of late I Na , appears to have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.

OBJECTIVESTo report the oncology and functional outcomes of transoral laser microsurgery (TLM) for untreated glottic carcinoma.STUDY DESIGNA 2 center prospective case series analysis.SETTINGAcademic, tertiary referral centers.RESULTSSeventy‐six patients underwent TLM. Pathologic T stages were: T1, 45 (59%); T2, 21 (28%); T3, 5 (7%); and T4, 5 (7%). Five (7%) patients had neck dissections. Five (7%) patients received adjuvant radiotherapy. Mean follow‐up was 42 months. Respective T1 and T2 5‐year Kaplan‐Meier estimates were: local control, 90% and 93%; loco‐regional control, 90% and 93%; disease specific survival, 90% and 93%; and overall survival, 94% and 93%. The average hospital stay was 2 days. Two (3%) patients experienced major complications. The overall laryngeal preservation rate was 95% (72 of 76).CONCLUSIONSTLM is a safe and effective treatment in select carcinoma of the glottic larynx. Low morbidity and mortality and short periods of hospitalization make TLM an attractive therapeutic option.SIGNIFICANCETLM is an emerging strategy in the treatment of laryngeal cancer.

AbstractHematopoietic stem cells (HSCs) can both self renew and differentiate into precursors of all types of blood cells. HSCs are divided into an active pool and a quiescent reserve. Cells selected for the active pool contribute to hematopoiesis for many years. Mutations in HSCs can lead to neoplasms such as chronic myeloid leukemia, although the risk of neoplastic HSC disorders varies across mammals. We use allometric scaling relations combined with mutation-selection evolutionary dynamics to determine which mammalian species is most resistant to HSC disorders. We find that the advantage of large mammals at escaping the selective pressure of cancer cells is insufficient to overcome the increased risk of acquiring mutations. Hence, mutation dominates, which favors smaller stem-cell pools and, consequently, smaller mammals, since these minimize the development of mutations in the active stem-cell pool. Consequently, the smaller the active stem-cell pools, the better.

Background and Purpose— Even though endovascular coils have been widely used for the treatment of intracranial aneurysms, the cellular and molecular responses of aneurysms to the coils after embolization remain poorly understood. The aim of the present study was to understand the mechanism of apoptosis in aneurysms embolized with platinum coils in the rabbit model of elastase-induced aneurysms. Methods— Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 30 rabbits. Aneurysms were allowed to mature for 8 weeks, after which 20 aneurysms were embolized with platinum coils by endovascular means. After 2 (n=10) and 4 (n=10) weeks of implantation, aneurysm samples harboring coils were harvested for apoptotic studies. The remaining 10 uncoiled aneurysms were used as controls; additional controls included the left common carotid artery, which had not undergone any surgical procedure. Control samples were harvested at 12 weeks after aneurysm creation. Results— Expression of procaspases-3, -8, and -9 was elevated in coiled aneurysms embolized with platinum coils at both time points when compared with uncoiled aneurysms and the left common carotid artery. Cleaved caspases-3, -8, and -9 were found to be expressed only at 4 weeks after embolization. Cells within the aneurysm cavity were terminal dUTP nick end-labeling–positive at 4 weeks only. These apoptotic cells were identified as smooth muscle actin–positive cells. Expression of tumor necrosis-α was high in coiled aneurysms when compared with controls. There was no significant difference in the expression of Fas ligand among groups. Decreased expression of antiapoptotic proteins Bcl-2 and phospho-Bad, as well as increased expression of proapoptotic proteins Bax and Bid, was observed in coiled aneurysms at both time points. Conclusions— Activation of apoptosis in aneurysms after embolization with platinum coils is induced by both tumor necrosis factor-α–mediated extrinsic and Bcl-2-mediated intrinsic pathways.

AbstractBackground: Assay of methylated DNA markers in stool is a promising approach for colorectal cancer (CRC) screening. A method to capture hypermethylated CpG islands from stool would enrich target analyte and allow optimal assay sensitivity.Methods: Methyl-binding domain (MBD) protein was produced using a pET6HMBD plasmid with MBD DNA sequence cloned from rat MeCP2 gene and bound to a column of nickel-agarose resin. We first established the feasibility of using the MBD column to extract methylated human DNA in a high background of fecal bacterial DNA. To explore the impact of MBD enrichment on detection sensitivity, the tumor-associated methylated vimentin gene was assayed with methylation-specific PCR from stools to which low amounts of cancer cell DNA (0–50 ng) were added and from stools from CRC patients and healthy individuals. Stools from cancer patients were selected with low amounts of human DNA (median 7 ng, range 0.5–832 ng).Results: With MBD enrichment, methylated vimentin was detected in stools enriched with ≥10 ng of cancer cell DNA and in CRC stool with a range of native human DNA amounts from 4 to 832 ng. Without MBD enrichment, methylated vimentin was not detected in the enriched stools and was detected in only 1 cancer stool with high human DNA (832 ng). In stools from healthy individuals methylated vimentin was not detected, with or without MBD enrichment.Conclusions: MBD capture increases assay sensitivity for detecting methylated DNA markers in stool. Applied clinical studies for stool cancer screening are indicated.